Schizophrenia is a severe mental illness that afflicts approximately one percent of the world's population. Although it is clear that approximately a half of the liability to develop the disorder is genetic, few genes have been unequivocally implicated in the etiology of the disorder. Recent data from a large (~3,000 cases and 3,000 controls) study of copy number variations in schizophrenia found evidence for three rare deletions on chromosomes 1q, 15q and 22p that may cause schizophrenia. The evidence from these deletions is insufficient to conclusively determine if they cause schizophrenia and, if they do, which of the deleted genes are responsible. We propose to determine the DNA sequence of the entire 5.3 Mb delineated by these three deletions in 1,000 individuals with schizophrenia and 1,000 controls to look for both common and rare variants in the deleted regions. The individuals to be sequenced will be chosen from the Portuguese Island Cohort (PIC). The DNA sequence data will be analyzed using logistic regression to determine regions of increased genetic variation in cases as compared to controls. These regions will then be genotyped in a larger sample of up to 20,000 cases and controls to determine which genes/regions in the deleted regions play a causative role in the development of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe mental illness that afflicts approximately one percent of the world's population. Although it is clear that approximately a half of the liability to develop the disorder is genetic, few genes have been unequivocally implicated in the etiology of the disorder. Recent data from a large (~3,000 cases and 3,000 controls) study of copy number variations in schizophrenia found evidence for three rare deletions on chromosomes 1q, 15q and 22p that may cause schizophrenia.